The recent dramatic progress in the field of prion diseases has opened up new possibilities to understand a number of lethal neurodegenerative disorders. Although the molecular biology of these diseases now are extensively analyzed, the discovery being the characterization of the prion protein, there is so far little information on the changes induced in the brain by this agent. Although the localization of the prion protein is now being analysed and although conventional histology has been carried out on several brain regions demonstrating marked spongiform neurodegeneration, for example in cortical and subcortical areas, there is virtually nothing known about the possible changes that may occur in the expression and distribution of neurotransmitters and their enzymes, neuropeptides, growth factors and the receptors for all these compounds. The project aims are to study with immunohistochemical, autoradiographic and in situ hybridization techniques a number of transmitters, transmitter enzymes, peptides and growth factors and their receptors in various brain regions of C57 BL6 (Prn-pa) mice inoculated with the Chandler isolate with aged matched controls inoculated with normal brain extracts. This will be carried out at various times, 0, 30, 60, 90, 120 days after inoculation, that is before clinical signs have appeared. We will initially concentrate on specific brain regions such as hippocampus, substantia nigra, locus coeruleus and the ventral forebrain and also start with a restricted number of marker molecules. Clearly, it is not possible at the moment to predict where changes can occur, so the initial phase will have the appearance of a screening study. Marked changes in one or more of the above mentioned markers have been observed in other neurodegenerative diseases such as Alzheimer's and Parkinson's disease. It seems therefore reasonable to pursue this line also for prion induced neurodegenerative diseases. The availability of transgenic mice offers a unique possibility to pursue this problem in a systematic and well controlled fashion. It is hoped that the planned studies will expand our knowledge of prion induced diseases and perhaps also give clues to our understanding of other neurodegenerative disorders.